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"Ebola hemorrhagic fever"
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Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial
TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated.
In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died.
Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls.
Pan African Clinical Trials Registry PACTR201501000997429.
Journal Article
Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates
Ebola-virus-targeting short interfering RNAs (siRNAs) encapsulated in lipid nanoparticles are adapted to the current outbreak strain of the virus, and the siRNA cocktail is shown to protect nonhuman primates fully when administered 3 days after challenge with the current West African Ebola virus isolate; upon viral sequence data availability, the drug can be adapted to the new virus and produced in as little as 8 weeks.
Treating the current Ebola outbreak
Ebola virus-targeting siRNAs encapsulated in lipid nanoparticles (TKM-Ebola) have been shown previously to provide post-exposure protection of nonhuman primates against lethal Ebola virus challenge. The therapy has also been used on compassionate grounds in a number of human patients in the current outbreak, although the efficacy in humans is not known. Here, Thomas Geisbert and colleagues rapidly adapt the TKM-Ebola cocktail to the current outbreak strain of the virus and show that it is able to fully protect nonhuman primates when administered 3 days after challenge with the current West African EBOV isolate. Once viral sequence data becomes available, the drug can be adapted to the new virus and produced in as little as 8 weeks.
The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled
1
. Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States
2
. However, the
in vivo
efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.
Journal Article
A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection
Ebola virus causes a devastating clinical illness that is associated with high mortality. In this trial conducted primarily in West Africa during an outbreak, ZMapp (a cocktail of three monoclonal antibodies against Ebola) showed some clinical activity.
The 2014–2016 Ebola outbreak in West Africa was unprecedented in sheer scope, duration, and number of human casualties.
1
,
2
The outbreak resulted in more than 28,000 suspected or confirmed cases of Ebola virus disease (EVD) and more than 11,000 deaths.
3
Fragile health care infrastructures that were often already severely compromised by past years of civil strife played a substantial role in the propagation of the outbreak. Although the final postmortem analysis of the global response has yet to be written, there can be little doubt that the lack of therapeutic agents and vaccines with proven efficacy against EVD further contributed . . .
Journal Article
Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone
In this report, the clinical presentation of some of the first cases of EVD occurring in the West African country of Sierra Leone are described, and factors associated with survival are characterized.
The largest and most widespread outbreak of Ebola virus disease (EVD) continues to spread through West Africa, with more than 10,100 cases reported in Guinea, Sierra Leone, Liberia, Senegal, Nigeria, and Mali as of October 25, 2014.
1
The possibility of global spread of the disease was realized recently with the diagnosis of EVD in patients in the United States and Spain.
2
The EVD outbreak appears to have originated near the town of Guéckédou, which is in the forest region of Guinea and close to the borders of Sierra Leone and Liberia.
3
,
4
Sequence analyses indicated that the West African variant . . .
Journal Article
Strengthening post-Ebola health systems : from response to resilience in Guinea, Liberia, and Sierra Leone
Addresses the challenge of enabling the development of viable, resilient, and fiscally sustainable health system in Guinea, Liberia, and Sierra Leone. Initiated while Ebola was still raging in all of the three most-affected countries in West Africa, the study identifies the requirements for strengthening the health systems in these countries to go beyond just getting the number of Ebola cases to zero. The overall goal of this study is thus twofold: To assess the capacity of the health systems of the three most-affected countries in terms of their ability to deliver quality health services to their populations, perform core public health functions on a routine basis, and to respond to public health emergencies; and To identify the highest impact strategies to help these countries to strengthen their health systems to be more effective and resilient, drilling down into three key aspects of the health system-- that is, fiscal space for universal health coverage (UHC), development and deployment of an effective health workforce, and continuous disease surveillance.-- Source other than the Library of Congress.
Book
Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp
Without an approved vaccine or treatments, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. Here we show that a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viraemia and abnormalities in blood count and blood chemistry were evident in many animals before ZMapp intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal haemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola. ZMapp exceeds the efficacy of any other therapeutics described so far, and results warrant further development of this cocktail for clinical use.
A new treatment, containing an optimized cocktail of three monoclonal antibodies against Ebola virus, provided full protection and disease reversal in rhesus monkeys when given under conditions in which controls succumbed by day 8; this new therapy may be a good candidate for treating Ebola virus infection in human patients.
Immunotherapy in advanced Ebola virus disease
This study shows that ZMapp, an optimized cocktail of three monoclonal antibodies that has been pressed into clinical use in response to the current Ebola virus disease epidemic, was able to rescue all of 18 rhesus macaques when treatment was initiated up to five days post-infection. All three controls had died by day eight.
Journal Article